Last Updated: 04/12/2025
Dissecting the mechanisms of infectivity in Plasmodium – experimental model of Plasmodium yoelii with implications for the study in Plasmodium vivax
Objectives
*Original title in Portuguese: Dissecando os mecanismos de infectividade em Plasmodium – modelo experimental de Plasmodium yoelii com implicações para o estudo em Plasmodium vivax
This project aims to expand the understanding of the mechanisms of pathogenesis and infectivity of Plasmodium using an experimental infection model with P. yoelii. It will investigate ligand / receptor interactions, identifying potential parasitic ligands and receptors for erythrocytes (mature or reticulocytes) involved in alternative invasion routes.
Plasmodium vivax is responsible for more than 80 million cases of malaria per year worldwide, with a strong social impact outside the African continent, mainly in Asia and the Americas. In addition, it has recently been found that, similarly to P. falciparum infections, P. vivax infections can also progress to severe forms of the disease. The entire invasion process is complex and involves several interactions between the parasite’s ligands and red blood cell receptors in a coordinated way. Current knowledge about the mechanisms and interactions during the invasion of erythrocytes by the parasite is limited, and this makes it difficult to develop approaches to block this essential pathway in maintaining the Plasmodium life cycle. Strategies capable of blocking the erythrocyte invasion are part of the rationale of several vaccines based on merozoite antigens. In this sense, methodologies designed to elucidate the phenomenon of invasion would facilitate the validation and identification of potential antigens that could be used as a target in the development of vaccines. Studies associated with the biology of P. vivax, its pathogenesis and infectivity are still incipient, mainly due to the difficulty of continuous cultivation of this parasite and the restriction of studies to laboratories in hospital centers located in endemic areas of malaria and that have an adequate installed infrastructure. P. vivax and P. yoelii use the Duffy antigen / receptor for chemokines (DARC) as a receptor for the invasion and both preferentially invade reticulocytes. Furthermore, since P. yoelii presents an alternative route of infection, presumably independent DARC, to invade reticulocytes and P. vivax also has an unknown mechanism to invade DARC negative reticulocytes, it is plausible to believe that alternative invasion routes can be shared by these two parasites. This project will assess the infectivity of different P. yoelii 17X transfectants with the gene corresponding to deleted surface proteins (EBP, DBL, MAEBL, AMA-1, Py235 and RON-2) in erythrocytes and reticulocytes from positive Duffy mice ( Dfy + / +) and negative Duffy (Dfy – / -). The evolution of infections, resulting from the different combinations of the new parasite populations with the target cells, will be analyzed to characterize the infected target cell populations (mature erythrocytes and reticulocytes) in Dfy – / – and Dfy + / = mice. Furthermore, to suggest an alternative invasion pathway to Duffy, we will study the parasite invasion in Dfy – / – erythrocytes treated with monoclonal antibodies specific for erythrocyte surface molecules.
Mar 2016 — Jun 2019
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